Integrin
From Wikipedia, the free encyclopedia
| integrin, alpha 1
| |
| Identifiers | |
| Symbol(s) | ITGA1 |
| Entrez | 3672 |
| OMIM | 192968 |
| RefSeq | NM_181501 |
| UniProt | [1] |
| Other data | |
| Locus | Chr. 5 q11.1 |
| integrin, beta 1
| |
| Identifiers | |
| Symbol(s) | ITGB1 FNRB, MSK12, MDF2 |
| Entrez | 3688 |
| OMIM | 135630 |
| RefSeq | NM_002211 |
| UniProt | P05556 |
| Other data | |
| Locus | Chr. 10 p11.2 |
An integrin, or integrin receptor, is an integral membrane protein in the plasma membrane of cells. It plays a role in the attachment of a cell to the extracellular matrix (ECM) and in signal transduction from the ECM to the cell. There are many types of integrin, and many cells have multiple types on their surface. Integrins are of vital importance to all metazoans, from humans to sponges.
Other types of protein that play a role in cell-cell/cell-matrix interaction and communication are cadherins, CAMs and selectins.
Contents |
[edit] Structure
Integrins are obligate heterodimers containing two distinct chains, called the α (alpha) and β (beta) subunits. About 18 α and 8 β subunits have been characterized. In addition, variants of some of the subunits are formed by differential splicing, for example 4 variants of the beta-1 subunit exist. Through different combinations of these alpha and beta subunits, some 24 unique integrins are generated.
Integrin subunits penetrate the plasma membrane, and in general have very short cytoplasmic domains of about 40-70 amino acids. The exception is the beta-4 subunit which has a cytoplasmic domain of 1088 amino acids, one of the largest known cytoplasmic domains of any membrane protein. Outside the cell plasma membrane, the alpha and beta chains lie close together along a length of about 23 nm, the final 5 nm NH2-termini of each chain form a ligand-binding region for the ECM.
The molecular mass of the integrin subunits can vary from 90 Kda to 160Kda. β subunits have four cysteine-rich repeated sequences. Both α and β subunits bind several divalent cations. The role of the α cations is unknown, but they may stabilize the folds of the protein. The β cations are more interesting: they are directly involved in coordinating at least some of the ligands that integrins bind.
There are various ways of categorizing the integrins. For example, a subset of the α chains has an additional structural cassette (or "domain") inserted toward the NH2-terminal, the so called alpha-A domain (because it has a similar structure to the A-domains found in the protein von Willenbrand factor). Integrins carrying this domain either bind to collagens (e.g. integrins α1 β1, and α2 β1), or act as cell-cell adhesion molecules (integrins of the β2 family). This α-I domain is the binding site for ligands of such integrins. The integrins that don't carry this inserted domain, also have an A-domain in their ligand binding site, but this A-domain is on the β chain.
In both cases, the A-domains carry up to three divalent cation binding sites. One of these sites is permanently occupied in physiological concentrations of divalent cations, and carries either a calcium or magnesium ion. The other two sites become occupied by cations when ligands bind - at least for ligands involving an acidic amino acid, usually aspartic acid, in their interaction sites. An acid amino acid features in the integrin-interaction site many ECM proteins, as part of the amino acid sequence Arginine-Glycine-Aspartic acid ("RGD" in the one-letter code).
X-ray crystal structure has been obtained for the complete extracellular and regions of one integrin, and this shows the molecule to be folded into an inverted V-shape which brings the ligand-binding sites close to the cell membrane. The current hypothesis is that integrin function involves changes in shape to move the ligand binding site into a more accessible position away from the cell surface, and this shape change also triggers intracellular signaling.
[edit] Function
Two main functions of integrins are:
- Attachment of the cell to the ECM.
- Signal transduction from the ECM to the cell.
However, they are also involved in a wide range of other biological activities. These include: binding of viruses, including adenovirus, Echo viruses, Hanta viruses, foot and mouth disease viruses, to cells; immune patrolling. Cell migration.
[edit] Attachment of cell to the ECM
Integrins couple the ECM outside a cell to the cytoskeleton (in particular the microfilaments) inside the cell. Which ligand in the ECM the integrin can bind to is mainly decided by which α and β subunits the integrin is made of. Among the ligands of integrins are fibronectin, vitronectin, collagen, and laminin. The connection between the cell and the ECM enables the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of bond is also of vital importance in ontogeny.
The connections between integrin and the ligands in the ECM and the microfilaments inside the cell are indirect: they are linked via scaffolding proteins like talin, paxillin and alpha-actinin. These act by regulating kinases like FAK (focal adhesion kinase)and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as Crk.
Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like VEGF, EGF and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the heart, both literally and figuratively, of cellular biological processes.
Recent studies have focused on the role of ECM to influence the cellular microenvironment and resulting cellular function. Not only are integrins used, but recent advances in synthetic ECM analogues - such as synthetic peptide nanofiber scaffolds - are allowing well-defined blank scaffolds to serve as the basis for carefully controlled microenvironments for these studies.
[edit] Signal transduction
Integrins play an important role in cell signaling. Connection with ECM molecules can cause a signal to be relayed into the cell through protein kinases that are connected with the intracellular end of the integrin molecule.
The signals the cell receives through the integrin can have relation to:
| Cell signaling |
|---|
| Key concepts - Ligand | Receptor | Second messenger | Protein kinase | Transcription factor | Cell signaling networks |
| Pathways - Apoptosis | Ca2+ signaling | Cytokine signaling | Hedgehog | Integrin signaling | JAK/STAT | Lipid signaling | MAPK/ERK pathway | mTOR | NF-kB | Notch | p53 | TGFβ | Wnt |
